NUTRIENT SENSING LABORATORY

Regulatory networks in sugar sensing

Sugars are highly energetic macronutrients and an essential part of diet for many animals. Excessive consumption of dietary sugars has been associated with increased risk for metabolic diseases in human. However, the genetic determinants that define the range of tolerated sugar intake and the individual's risk for metabolic disturbance on high sugar diet are poorly understood. Nutrient sensing pathways are needed to readjust metabolic pathways in response to changes in nutrient intake. We aim to understand how gene expression is regulated in response to dietary sugars and how these genetic responses influence animal physiology.

Our recent work has focused on the physiological role of Mondo (ChREBP) –Mlx, which is a heterodimeric transcription factor complex mediating intracellular sensing of sugar metabolites. We have discovered that loss of Mondo-Mlx leads to striking sugar intolerance in Drosophila (Havula et al., 2013). A genome-wide analysis of Mondo-Mlx targets have shown that it is responsible for the regulation of a majority of sugar-regulated genes in Drosophila, controlling metabolic gene expression in multiple tissues, including fat body, gut and renal tubules (Mattila et al., 2015). In addition of metabolic targets, our work has revealed that Mondo-Mlx is a master regulator of a sugar-sensing regulatory network, including other transcription factors, such as Cabut (Klf10) and Sugarbabe (Gli similar) (Bartok et al., 2015; Mattila et al., 2015) (Figure 1). Mondo-Mlx is also interconnected with hormonal signaling, as it regulates the sugar-inducible expression of TGF-beta/Activin ligand Dawdle (Mattila et al., 2015).

Figure 1. Mondo-Mlx is a master regulator of a sugar-sensing regulatory network, including transcription factors Cabut and Sugarbabe as well as TGF-beta/Activin ligand Dawdle.

In addition to metabolic pathway activities, redox balance needs to be closely controlled in response to sugar feeding. Our recent work has shown that a key regulator of NADPH redox balance is protein kinase SIK3 (Teesalu et al., 2017). SIK3 phosphorylates the rate-limiting enzyme of the pentose-phosphate pathway, which maintains NADPH redox balance (Figure 2). Loss of SIK3 leads to oxidative stress on high sugar diet and loss of sugar tolerance. Interestingly, SIK3 converges with Mondo-Mlx to maintain sugar tolerance, as Mondo-Mlx promotes the pentose phosphate pathway transcriptionally (Mattila et al., 2015).

Figure 2. SIK3 and Mondo-Mlx synergize to control the pentose phosphate pathway, which maintains redox balance upon sugar feeding.

Our current work is focusing on exploring the roles new regulatory genes, which act downstream or synergistically with Mondo-Mlx to control metabolic readjustment in response to sugar feeding. We are also exploring whether the mechanisms we have discovered contribute to pathophysiologies in human, including, fatty liver disease, high circulating triglyceride levels as well as cancer.

Novel regulators and effectors of insulin-like signaling

Insulin-like signaling regulates growth, energy metabolism, longevity, and reproductive functions in response to organismal nutrient status. Drosophila has a single insulin-like receptor, which is activated by several insulin-like peptides (dILPs). Secretion and expression of dILPs are controlled by nutrient status. Insulin-like receptor activates a number of conserved signaling pathways, most notably the PI3K/AKT and TOR pathways. Activities of these nutrient-regulated signaling pathways are key regulators of tissue growth and they determine the eventual body size of the animal.

By performing a genetic screen in the Drosophila insulin-producing cells (IPCs) we recently discovered a key role for an atypical MAP kinase ERK7 (ERK8/MAPK15) in insulin-like peptide (ILP) secretion. ERK7 is activated by starvation and it blocks the secretion of ILP2 and ILP5 in the IPCs. Consequently, ERK7 inhibits organismal growth (Hasygar & Hietakangas, 2014). Our current work focuses on understanding the in vivo roles of ERK7 more globally as well as on exploring the functions of novel downstream effectors of the insulin signaling pathway.

Contact information

Ville Hietakangas
Group leader, PhD
Associate Professor
Tel. +358 2941 58001
e-mail: ville.hietakangas (at) helsinki.fi

Department of Biosciences (Genetics)
Institute of Biotechnology
P.O.Box. 56, 00014 University of Helsinki
Street address: Viikinkaari 9, Biocenter 1